N-Substituted phenyl-5-aminomethyl oxazolidinones and their method of use

ABSTRACT

N-aryl oxazolidinones, oxazolidinethiones, pyrrolidinones, pyrrolidines and thiazolidinones are disclosed. These compounds possess antidepressant activity.

This is a division of application Ser. No. 45,143 filed June 4, 1979,now U.S. Pat. No. 4,348,393, issued 9-7-82.

The present invention relates to N-aryl oxazolidinones,oxazolidinethiones, pyrrolidinones, pyrrolidines and thiazolidinones,their process of preparation and their therapeutic application.

The compounds of the invention have the formula: ##STR1## in which theparameters (X, A, R₁) take anyone of the following values:

(a) (O,O,H), R₂ is:

either an ester group of formula --CH₂ --OCOR₃ in which R₃ is a linearor branched alkyl moiety having from 1 to 8 carbon atoms, a cyclohexylgroup, a phenyl nucleus, a methoxymethyl or a phenyloxymethyl group; andR is in para position and is anyone of the following groups: n-butyloxy,methyl-3 butyloxy, cyclopentylmethoxy, cyclohexylmethoxy, cyano-2ethoxy, cyanomethoxy, benzyloxy of formula ##STR2## in which R₄ is ahydrogen or a chlorine atom in meta position, a fluorine atom in meta orpara position, or a cyano or nitro group in meta position; disubstitutedpara-benzyloxy group of formula ##STR3## in which R₅ is a chlorine atomor a cyano group; or an ether group of formula --CH₂ --OR₆ in which R₆is a linear or branched alkyl group having from 1 to 5 carbon atoms, acyclohexyl, allyl, propargyl or methoxymethyl group; and R is the methylgroup in meta position, or is any one of the following groups located inpara position:

linear or branched alkyloxy having from 4 to 6 carbon atoms,

cycloalkylmethyloxy the cycloalkyl moiety of which has from 4 to 7carbon atoms,

(methyl-1 cyclopentyl-1)methyloxy,

(cyclopentene-1 yl)methyloxy,

(cyclohexene-1 yl)methyloxy,

(butene-2)oxy,

(methyl-3 butene-2)oxy,

chloro-4 butyloxy,

cyano-2 ethoxy; cyano-3 propoxy or cyano-4 butoxy,

oxo-2 propoxy,

(oxo-4 cyclohexyl-1)methoxy,

morpholino-2 ethoxy,

N,N dimethyl amino,

(tetrahydropyranyl-4)methoxy or (tetra hydropyranyl-3)methoxy,

benzyloxy of formula ##STR4## in which R₇ is selected from the groupconsisting of: H, 3-Cl, 4-Cl, 3-F, 4-F, 3-I, 3-Br, 3-CF₃, 3-NO₂, 4-NO₂,4-CN,

3-cyanobenzyloxy, the corresponding compound of formula (I) having anasymmetric carbon being isolated as a racemic mixture or as twoenantiomers or formulae (Ia) and (Ib) having respectively the absoluteconfiguration: R(-) and S(+) ##STR5## disubstituted benzyloxy of formula##STR6## in which R₈ is a chlorine atom, or a cyano or nitro group;disubstituted benzyloxy of formula ##STR7## in which R₉ is a chlorineatom or a nitro group; disubstituted benzyloxy of formula ##STR8## inwhich R₅ is a a chlorine atom or a cyano group; 3,5-dichlorobenzyloxy;

substituted or non substituted styryl chain of trans configuration andof formula ##STR9## in which R₁₀ is a hydrogen or chlorine atom, or acyano or nitro group;

substituted or non substituted styryl chain of cis configuration and offormula ##STR10## in which R₁₁ is a hydrogen atom or a nitro group,##STR11## or phenethyl chain, or phenyl nucleus;

or an amine group of formula ##STR12## is selected from the groupconsisting of: --NH₂, NH--CH₃, NH--C₂ H₅, NH--<, ##STR13## and R is inpara position and is selected from the group consisting of: n-butyloxy,methyl-3 butyloxy, cyclopentylmethoxy, cyclohexylmethoxy, cyanomethoxyor cyano-2 ethoxy group;

benzyloxy group of formula ##STR14## in which R₁₄ has one of thefollowing values: H, 3-Cl, 4-F, 3-CN, 3-NO₂ ; or

disubstituted benzyloxy group of formula ##STR15##

(b) (O,CH₂,H), R₂ is the hydroxymethyl group, and R is thepara-(metanitro)benzyloxy group;

(c) (H₂,CH₂,H), R₂ is the hydroxymethyl group and R is the parabenzyloxygroup;

(d) (O,S,H), R₂ is the methoxymethyl group and R is thepara-(metanitro)benzyloxy group;

(e) (S,O,H), R₂ is:

either a hydroxymethyl group and R in para position is selected from thegroup consisting of:

a linear or branched alkyloxy group having from 2 to 5 carbon atoms,

a cyclopentylmethoxy, cyclohexylmethoxy, (cyclohexene-1 yl)methoxy or(tetrahydropyranyl-4)methoxy group,

a cyanomethoxy, cyano-2 ethoxy, cyano-3 propoxy or cyano-4 butoxy group,

a benzyloxy group of formula ##STR16## in which R₁₅ has one of thefollowing values: 3-Cl, 4-Cl, 3-F, 4-F, 3-NO₂, 3-CN, 3-CF₃, or

a disubstituted benzyloxy group of formula: ##STR17## or an ether groupof formula --CH₂ --O--R₁₆ in which R₁₆ is a linear or branched alkylgroup having from 1 to 3 carbon atoms, and R in para position isselected from the group consisting of:

methyl-3 n-butyloxy, cyclopentylmethoxy, cyclohexylmethoxy or cyano-4butoxy group),

a benzyloxy group of formula ##STR18## in which R₁₇ is a cyano or nitrogroup, the cyano-3 nitro-5 benzyloxy group, or

the pyridinyl-3 methoxy group,

or an ester group of formula --CH₂ --OCOR₁₈ in which R₁₈ is a methyl orethyl group and R in para position is the cyclohexylmethoxy group or abenzyloxy group of formula ##STR19## in which R₁₇ is a cyano or nitrogroup.

(A) The process for preparing the compounds of formula (I) in which theparameters (X,A,R₁,R₂) represent (O,O,H, CH₂ OCOR₃), R₃ having the samemeanings as above, consists in condensing the compounds of formula:##STR20## in which R₁₉ represents one of the following groups:n-butyloxy; methyl-3 butoxy; cyclopentylmethoxy; cyclohexylmethoxy;cyano-2 ethoxy; cyanomethoxy; benzyloxy of formula ##STR21## with R₄ =H,3-Cl, 3-F, 4-F, 3-CN or 3-NO₂ ; and benzyloxy of formula ##STR22## withR₅ =Cl or CN, with the acid chlorides of formula:

    R.sub.3 COCl                                               (III)

in which R₃ has the same meanings as above.

This condensation is carried out preferably at room temperature, eitherin an organic solvent such as chloroform or tetrahydrofuran in thepresence of triethylamine, or in pyridine.

The compounds of formula (II), except those in which R₁₉ is the cyano-2ethoxy group, are prepared according to the method described in BelgianPat. No. 851 893 (reacting the p-hydroxyphenyl-3 hydroxymethyl-5oxazolidinone-2 on the suitable chloride, bromide or tosylate).

The compound of formula (II) in which R₁₉ is the cyano-2 ethoxy group isobtained by cyclising, by action of ethyl carbonate, the compound offormula ##STR23## to obtain the compound of formula: ##STR24## which isselectively hydrogenolysed in the presence of palladium on charcoal, inethanol, preferably at room temperature, to give the compound offormula: ##STR25## which is condensed with acrylonitrile in the presenceof triton B, to give the compound of formula: ##STR26## which is thenhydrogenolysed in ethanol in the presence of palladium on charcoal, andpreferably, of some drops of hydrochloric ethanol.

The compound of formula (IV) is obtained in condensing, in methanol orethanol, the parabenzyloxyaniline with the benzyloxy-3 epoxy-1,2propane.

(B) The process for preparing the compounds of formula (I) in which theparameters (X,A,R₁) represent (O,O,H), and R₂ is an ether group offormula --CH₂ --OR₆ in which R₆ has the same meanings as above consists:

(1) either in submitting the compounds of formula: ##STR27## in whichR₂₀ represents the meta-methyl group or one of the following groups inpara position: linear or branched alkyloxy having from 4 to 6 carbonatoms; cycloalkylmethoxy the alkyl moiety of which has from 4 to 7carbon atoms; (methyl-1 cyclopentyl-1)methoxy; butene-2 oxy; methyl-3butene-2 oxy; (cyclopentene-1 yl)methoxy; (cyclohexene-1 yl)methoxy;morpholino-2 ethoxy; chloro-4 butyloxy; (oxo-4 cyclohexyl-1)methoxy;oxo-2 propoxy; cyano-3 propoxy; cyano-2 ethoxy; cyano-4 butoxy: dimethylamino; (tetrahydropyranyl-4)methoxy; (tetrahydropyranyl-3)methoxy;benzyloxy of formula ##STR28## in which R₇ =H, 3-Cl, 4-Cl, 3-F, 4-F,3-I, 3-Br, 3-CF₃, 3-NO₂, 4-NO₂, 3-CN, 4-CN; disubstituted benzyloxy offormula: ##STR29## in which R₈, R₉ and R₅ have the same meanings asabove; and ##STR30## to a so-called "phase transfer" reaction, in thepresence of a catalyst so-called "phase transfer catalyst", and in abasic medium with derivatives of formulae:

    (CH.sub.3).sub.2 SO.sub.4

    R.sub.6 --Cl or

    R.sub.6 --I

in which R₆ has the same meanings as previously.

The used catalyst is preferably the benzyltributylammonium bromide, butit can be chosen among the catalysts mentioned in the followingdocuments: Synthesis 1973, 441, and Angewandte Chemie, Edit. Int. Vol.13, 170, (1974).

The used base is preferably aqueous soda and the reaction can be carriedout in an organic solvent such as methylene chloride or benzene.

The compounds of formula (IIa), except those in which R₂₀ represents thecyano-2 ethoxy group which is obtained by hydrogenolysing the compoundfor formula (VII), are prepared according to the method described inBelgian Pat. No. 851 893.

(2) or in condensing the compounds of formula: ##STR31## in which R'₆ isa linear or branched alkyl group having from 1 to 5 carbon atoms, acyclohexyl or a methoxymethyl group, with the chlorides or tosylates offormula:

    R'.sub.20 --Cl

    R'.sub.20 --OTs

in which R'₂₀ has the same meanings as R₂₀ except for the meta-methyland para-cyano-2 ethoxy groups.

The condensation is carried out with reflux in acetone or acetonitrilein the presence of potassium carbonate, or with reflux indimethylformamide in the presence of sodium hydride.

The compounds of formula (VIII) are obtained by hydrogenolysing in thepresence of palladium on charcoal, the compounds of formula: ##STR32##in which R'₆ has the same meanings as in formula (VIII).

The compounds of formula (IX) are obtained by a three stages synthesiswhich consists in condensing the chlorhydrine of formula: ##STR33## inwhich R'₆ has the same meanings as in formula (IX) with phosgene, thenin condensing the product thus obtained with parabenzyloxyaniline and atlast in cyclising the obtained product by means of ethanolic potash orsodium methylate in methanolic solution.

(3) or, when R is the cyano-2 ethoxy group, in reacting acrylonitrile inthe presence of triton B with the compound of formula (VIII);

(4) or, according to the process described above for the synthesis ofcompounds of formula (IX), but with chlorohydrines of formula (X) andanilines of formula: ##STR34## in which R₂₁ represents a trans styrylgroup of formula ##STR35## with R₁₀ =H, Cl, CN, NO₂ ; a cis styryl groupof formula ##STR36## with R₁₁ =H, NO₂ ; a stylbene group ##STR37## aphenethyl group; or a phenyl group; instead of the parabenzyloxyaniline;

(5) or, when (I) is (Ia) in submitting to a "phase transfer" reactionthe compound of absolute configuration R(-) and having the formula:##STR38## in presence of a phase transfer catalyst, of (CH₃)₂ SO₄ and ina basic medium.

The compound of formula (IIb) is obtained by reacting themetacyanobenzyl chloride with the compound of formula: ##STR39## whichis obtained by hydrogenolysing in the presence of palladium on charcoal,the compound of absolute configuration R(-) and having the formula:##STR40##

This last compound is obtained according to the method described for thesynthesis of compounds of formula (IX) but from parabenzyloxyaniline andbenzyloxy-3 paratosyloxy-1 propanol-2 having the S(+) configuration,instead of the compound of formula (X).

(6) or, when (I) is (Ib), according to the process described for thesynthesis of compounds of formula (IX), but by using thep-(cyano-3)benzyloxyaniline instead of parabenzyloxyaniline andmethoxy-3 paratosyloxy-1 propanol-2 of absolute configuration R and offormula: ##STR41## instead of the compound of formula (X).

The compound of formula (XII) is obtained by reacting the tosylchloride, in a benzene medium and in the presence of pyridine, with themethoxy-3 propane diol-1,2 of absolute configuration S and of formula:##STR42##

This compound of formula (XIII) is obtained by catalyticallydebenzylating, in the presence of palladium on charcoal, the compound ofabsolute configuration R and of formula: ##STR43##

The compound of formula (XIV) is obtained by opening, with methanol inthe presence of boron trifluoride etherate, benzyloxy-1 epoxy-2,3propane having the absolute configuration S(+) and described in J. Chem.Soc. 1967 1021.

(C) The process for preparing the compounds of formula (I) in which theparameters (X,A,R₁) represent (O,O,H), R₂ represents an amine group offormula ##STR44## has the same meanings as above, consists in reactingamines of formula ##STR45## with the compounds of formula: ##STR46## inwhich R₂₂ is a n-butyloxy, methyl-3 butyloxy, cyclopentylmethoxy,cyclohexylmethoxy, cyanomethoxy, cyanoethoxy group, benzyloxy group offormula ##STR47## in which R₁₄ has the same meanings as above or achloro-3 nitro-5 benzyloxy group.

The compounds of formula (XV) are obtained by action of mesyl chlorideon the compounds of formula: ##STR48## in which R₂₂ has the samemeanings as in formula (XV), the compounds of formula (IId) beingobtained according to the process described in Belgian Pat. No. 851 893.

(D) The process for preparing the compounds of formula (I) in which theparameters (X, A, R₁) represent (O,CH₂,H), R₂ represents thehydroxymethyl group and R represents the para(metanitro)benzyloxy groupconsists in reacting the metanitrobenzyl chloride on the compound offormula: ##STR49## obtained by hydrogenolysing in the presence ofpalladium on charcoal, the compound of formula: ##STR50## obtained byreducing with lithium borohydride the compound of formula: ##STR51##

The compound of formula (XVIII) is obtained by esterifying with ethanolin the presence of sulfuric acid, the compound of formula: ##STR52##which is obtained by condensing parabenzyloxyaniline with itaconic acid.

The process for preparing the compound of formula (I) in which (X,A,R₁)is (H₂, CH₂,H), R₂ is the hydroxymethyl group and R is the parabenzyloxygroup consists in reducing with lithium aluminium hydride the compoundof formula (XVIII).

(E) The process for preparing the compound of formula (I) in which (X,A,R₁) is (O,S,H), R₂ is the methoxymethyl group and R is thepara(metanitro)benzyloxy group consists in cyclising with the phosgenethe compound of formula: ##STR53## obtained by condensingpara(metanitro)benzyloxyaniline with methoxy methyl-2 thiooxirane.

(F) The process for preparing the compounds of formula (I) in which theparameters (X,A,R₁) are (S,O,H), R₂ is a hydroxymethyl group or a --CH₂OR₁₆ group in which R₁₆ has the same meanings as above, consists incyclising with thiophosgene,

either compounds of formula: ##STR54## in which R₂₃ represents linear orbranched alkyloxy group having from 2 to 5 carbon atoms,cyclopentylmethoxy, cyclohexylmethoxy, (cyclohexene-1 yl)methoxy,(tetrahydropyrannyl-4)methoxy, cyanomethoxy, cyano-2 ethoxy, cyano-3propoxy, cyano-4 butoxy group, benzyloxy group of formula ##STR55## withR₁₅ =3-Cl, 4-Cl, 3-F, 4-F, 3-NO₂, 3-CN or 3-CF₃, (chloro-3cyano-5)benzyloxy or (cyano-3 fluoro-4)benzyloxy group,

or compounds of formula: ##STR56## in which R₁₆ has the same meanings asabove and R₂₄ represents a methyl-3 butoxy; cyclopentylmethoxy,cyclohexylmethoxy, cyano-4 butoxy group, a benzyloxy group of formula##STR57## with R₁₇ =CN or NO₂, a (cyano-3 nitro-5)benzyloxy or(pyridinyl-3)methoxy group.

The compounds of formula (XXI) are obtained by condensing glycidol andanilines of formula: ##STR58## in which R₂₃ has the same meanings as informula (XXI), and the compounds of formula (XXII) are obtained bycondensing anilines of formula: ##STR59## in which R₂₄ has the samemeanings as in formula (XXII) with the chlorohydrines of formula:##STR60## in which R₁₆ has the same meanings as above.

(G) The process for preparing the compounds of formula (I) in which theparameters (X,A,R₁) represent (S,O,H) and R₂ is an ester group offormula R₁₈ COOCH₂ in which R₁₈ has the same meaning as above, consistsin condensing the acid chloride of formula:

    R.sub.18 COCl                                              (IIIa)

in which R₁₈ is as above, with the compounds of formula (I) having thefollowing structure: ##STR61## in which R₂₅ represents acyclohexylmethoxy group or a benzyloxy group of formula ##STR62## withR₁₇ =CN or NO₂, according to the process described under chapter (A)above. The compounds (Ic) are obtained according to the processdescribed under chapter (F) above.

The following preparations are given by way of example to illustrate theinvention.

EXAMPLE I Para (meta-nitrobenzyloxy)phenyl-3 acetoxy-methyl-5oxazolidinone-2 [I] Code number: 36

A solution of 10.5 g of para(metanitrobenzyloxy)phenyl-3 hydroxymethyl-5 oxazolidinone-2 [(II), mp=135° C.], 2.5 cm³ of acetyl chlorideand 4.5 cm³ of triethylamine in 100 cm³ of chloroform was left for 12hours at room temperature. Then, the solution was diluted in water, thechloroformic phase was decanted, the solvent was evaporated and theresidue was recrystallized in pure alcohol. 8 g of product wereobtained.

Yield: 72%

Melting point: 126° C.

Empirical formula: C₁₉ H₁₈ N₂ O₇

Molecular weight: 386.35

Elementary Analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 59.06        4.70   7.25    Found (%)    59.10        4.56   6.95    ______________________________________

With the same method, but from the corresponding reagents, the compoundsof formula (I) were prepared, given in table I and bearing code numbers:1 to 44; 103 to 108; 115, 117, 120 to 141; 178 and 208.

EXAMPLE 2 (paracyano-2 ethoxyphenyl)-3-hydroxymethyl-5 oxazolidinone-2[II] ##STR63## First step: (p-benzyloxyphenyl)-3 benzyloxymethyl-5oxazolidinone-2 (V)

This compound was obtained following a method in which a mixture of 0.2mole of the compound of formula: ##STR64## 200 ml of ethyl carbonate and8 ml of triethylamine is heated at 100°-110° C. for 5 hours, then theproduct was filtered and recrystallized in pure alcohol.

Yield: 80%

Melting point: 126° C.

Empirical formula: C₂₄ H₂₃ NO₄

Molecular weight: 389.43

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 74.02        5.95   3.60    Found (%)    73.87        6.14   3.89    ______________________________________

Second step: (p-hydroxyphenyl)-3 benzyloxymethyl-5 oxazolidinone-2 (VI)

A suspension of 18 g (0.046 mole) of the compound obtained in the firststep and 2 g of 10% palladium charcoal in 400 ml of pure alcohol washydrogenolysed in autoclave, at room temperature and under a hydrogenpressure of 4-5 kg. Then the mixture was filtered, the solventevaporated and the residue recrystallized in pure alcohol.

Yield: 73%

Melting point: 153° C.

Empirical formula: C₁₇ H₁₇ NO₄

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 68.21        5.73   4.68    Found (%)    68.38        5.62   4.46    ______________________________________

By the same process, but from the corresponding reagents, the compoundof formula (IIc) [mp=188° C., Empirical formula: C₁₀ H₁₁ NO₄ ] (fromcompound of formula (Va)); and the compound of formula (XVI) [mp=196°C., empirical formula: C₁₁ H₁₃ NO₃ ] (from compound of formula (XVII))were obtained.

Third step: (p-cyanoethoxy-2 phenyl)-3 benzyloxymethyl-5 oxazolidinone-2(VII)

A solution of 13 g (0.03 mole) of the compound prepared in the secondstep, in 45 g (0.86 mole) of acrylonitrile in the presence of 1 ml oftriton B (40% in methanol), was brought to reflux for 15 hours. Then theacrylonitrile in excess was evaporated, the residue was taken up in 100ml of N soda and filtered, the precipitate was washed with water thenwith ether and recrystallized in methanol.

Yield: 60%

Melting point: 112° C.

Empirical formula: C₂₀ H₂₀ N₂ O₄

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 68.17        5.72   7.95    Found (%)    67.89        5.66   8.21    ______________________________________

By the same method, but from the corresponding reagents, the compoundsof formula (I) were prepared, given in table (I) and bearing codenumbers 52 to 54 and 145 to 147.

Fourth step: (p-cyano-2 ethoxyphenyl)-3 hydroxymethyl-5 oxazolidinone-2(II) ##STR65##

A suspension of 3.5 g (0.01 mole) of (p-cyano-2ethoxyphenyl)-3-benzyloxymethyl-5 oxazolidinone-2, obtained in thepreceding step, 0.4 g of 10% palladium charcoal and 0.05 ml of 7.5Nchlorhydric ethanol in 250 ml of dioxane, was hydrogenolysed in anautoclave, at a pressure of 1 kg of hydrogen and at room temperature.The mixture was filtered, the residue was purified by chromatography ona silica column. Eluted with the mixture chloroform-acetone 50/50, theproduct was obtained which was recrystallized in pure alcohol. Weight: 1g.

Yield: 39%

Melting point: 131° C.

Empirical formula: C₁₃ H₁₄ N₂ O₄

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 59.53        5.38   10.68    Found (%)    59.06        5.24   10.37    ______________________________________

EXAMPLE 3 para (meta-nitrobenzyloxy) phenyl-3 methoxymethyl-5oxazolidinone-2 (I) Code number: 61

A mixture of 10.3 g of para (metanitrobenzyloxy) phenyl-3hydroxymethyl-5 oxazolidinone (IIa), 10.7 g of benzyltributylammoniumbromide, 14.2 g of methyl iodide and 1.8 g of NaOH in 200 ml of waterand 280 ml of methylene chloride, was brought to reflux for 50 hours.Then the mixture was decanted, the organic layer washed with water, thesolvent evaporated, the residue taken up in ethyl acetate, the filtratewas filtered and chromatographied on a silica column; eluted withchloroform, 6.9 g of the product was obtained which was recrystallizedin isopropanol.

Yield: 62%

Melting point: 78° C.

Empirical formula: C₁₈ H₁₈ N₂ O₆

Molecular weight: 358.34

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 60.33        5.06   7.82    Found (%)    60.52        5.10   7.92    ______________________________________

By the same method, but from the corresponding reagents, the compoundsof formula (I) were prepared, given in table (I) and bearing codenumbers 45, 46, 55 to 57; 59, 64 to 73; 109 to 112; 142 to 156; 159 to169; 179 to 186; 188, 197, 198 and 199 (Ia)

EXAMPLE 4 para-n-butyloxy phenyl-3-isopropyloxymethyl-5 oxazolidinone-2(I) Code number: 47 First step: para benzyloxyphenyl-3 isopropyloxymethyl-5 oxazolidinone-2 (IX) Code number: 225

To a solution of 59 g of phosgene in 560 ml of dichloroethane was added83.4 g of chloro-1 isopropyloxy-3 propanol-2 (X), then in 30 minutes asolution of 81.9 g of N,N-diethylaniline in 160 ml of dichloroethane.The mixture was heated to 50° C. for 2 hours, 250 ml of water was added,the organic layer was decanted and added in 30 minutes on 217.5 g ofpara benzyloxyaniline. The mixture was brought to reflux for 3 hours,filtered, washed with a 1N hydrochloric acid solution, with water,dried, the solvent was evaporated and the residue was recrystallized inethanol. 165.5 g of the product were obtained.

Yield: 81%

Melting point: 107° C.

NMR spectrum: δppm (DMSO):

    ______________________________________    9.80,s, NHCOO            1 proton    7.40,s, and 5.08,s:      7 protons    7.18,m, aromatic protons 4 protons     ##STR66##               1 proton     3.85,d, (J = 5Hz) CH.sub.2O                             2 protons    3.59,m, ClCH.sub.2CH     3 protons     ##STR67##               6 protons    ______________________________________

IR spectrum: band NH--COO at 1700 and 3305 cm⁻¹

A solution of 165.5 g of this compound and 29.3 g of potash in 2.4liters of ethanol was brought to 50° C. for 3 hours. Then the solventwas evaporated, the residue was taken up in chloroform, washed withwater, dried and the solvent was evaporated. The residue wascrystallized in ether and recrystallized in dioxan. 113 g of productwere obtained.

Yield: 75%

Melting point: 110° C.

Empirical formula: C₂₀ H₂₃ NO₄

Molecular weight: 341.4

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 70.36        6.79   4.10    Found (%)    70.14        6.49   4.22    ______________________________________

By the same method, but from the corresponding reagents, the compoundsof formula (IX) were prepared, given in table (II) and bearing codenumbers 226 to 229; as well as:

the compounds of formula (I) given in table I and bearing code numbers187,189 to 196,

the compound of formula (Ib) given in table I and bearing code number20, and

the compound of formula (Va): mp=100° C.; Yield: 93%;

Empirical formula: C₂₄ H₂₃ NO₄ ; [α]_(D) ²¹ =-33°5 (C=1, CH₂ Cl₂)

Second step: parahydroxyphenyl-3 isopropyloxymethyl-5 oxazolidinone-2(VIII) Code number: 221

85 g of the compound prepared in the first step in 1700 ml of dioxaneand 15 ml of 6.5N hydrochloric alcohol, in the presence of 8.5 g of 10%palladium charcoal, were hydrogenolysed in an autoclave at a pressure of6 kg for 6 hours. Then the mixture was filtered, the solvent wasevaporated, the residue was crystallized in ether and recrystallized intoluene. 43.7 g of product were obtained.

Yield: 70%

Melting point: 93° C.

Empirical formula: C₁₃ H₁₇ NO₄

Molecular weight: 251.3

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 62.14        6.82   5.57    Found (%)    62.14        6.80   5.56    ______________________________________

By the same method, but from the corresponding reagents, the compoundsof formula (VIII) were prepared, given in table III and bearing codenumbers: 222 to 224 and 230 to 232.

Third step para n-butyloxyphenyl-3 isopropyloxy methyl-5 oxazolidinone-2(I) Code number: 47

To a solution of 8.7 g of the compound obtained in the preceding step in150 ml of dimethyl formamide, was added 1.68 g of sodium hydride (50%),then 9.7 g of n-butyl chloride. The mixture was brought to 100° C. for 2hours and 30 mn, then the solvent was evaporated, the residue was takenup in chloroform, washed with water, dried, the solvent was evaporated,the residue was crystallized in isopropyl ether and recrystallized inisopropanol. 7.8 g of product were obtained.

Yield: 73%

Melting point: 77° C.

Empirical formula: C₁₇ H₂₅ NO₄

Molecular weight: 307.4

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 66.42        8.20   4.56    Found (%)    66.19        8.27   4.36    ______________________________________

By the same method, but from the corresponding reagents, the compoundsof formula (I) were prepared, given in table I and bearing the followingcode numbers: 48, 50, 51, 58, 60, 62, 63, 142, 143, 152, 153, 157, 158,160, 99 and 234, as well as the compound of formula (IIb): mp=132° C.;Yield: 97%; [α]_(D) ²⁰ =-79°2 (C=1, pyridine): Empirical formula: C₁₈H₁₆ N₂ O₄ ; Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 66.66        4.97   8.64    Found (%)    66.54        5.01   8.54    ______________________________________

EXAMPLE 5 p-toluene sulfonyloxy-1 hydroxy-2 methoxy-3 propane (Rconfiguration) (XII) First step: methoxy-1 hydroxy-2 benzyloxy-3 propaneR (+)(XIV)

To a solution of 4.14 g of benzyloxy-3 epoxy-1,2 propane in 40 ml ofmethanol, cooled to 5° C., were added 3 drops of boron trifluorideetherate. Then the mixture is left so as to reach slowly the roomtemperature (3 hours). A few gms sodium bicarbonate was added, thesolvent was evaporated, the residue was taken up in 200 ml of water,extracted with methylene chloride, dried on sodium sulfate and thesolvent was evaporated. The residue was chromatographed by highperformance liquid chromatography (HPLC) (SiO₂ 15-25μ), the elutionagent being a mixture of ethyl acetate (60%) and n-heptane (40%), anddistillated BP₀.1 =175° C. 70% of product were obtained.

[α]_(D) ²⁰ =+44°3 (C=5, ethanol). Empirical formula: C₁₁ H₁₆ O₃

Second step: methoxy-3 propane diol-1,2 (S) (XIII)

A solution of 4.44 g of the compound obtained in the first step, in 200ml of ethanol and 1 drop of hydrochloric ethanol, was hydrogenolised ata pressure of 5 kg and a temperature of 30° C., in the presence of 10%palladium charcoal. Then the mixture was filtered, a few gms bicarbonatewas added to the filtrate, the solvent was evaporated, the residue wastaken up in ether, washed with water, dried on sodium sulfate, and thesolvent was evaporated. 2.37 g of product were obtained after HPCL(SiO₂) of the crude product, the elution agent being a mixture ofethylacetate (60%) and n-heptane (40%).

Third step: toluene sulfonyloxy-1 hydroxy-2 methoxy-3 propane (R) (XII)

To a solution of 2.37 g of the compound obtained at the preceding step,in 10 ml of pyridine, cooled at 0° C., was slowly added a solution of4.27 g of tosyl chloride in 50 ml of benzene. Then the mixture was leftfor 40 hours at room temperature, diluted with ether, filtered and thefiltrate was washed with 1N hydrochloric acid, then with water and withan aqueous solution of sodium bicarbonate until neutrality. Then it wasdried on sodium sulfate and the solvent was evaporated. The residue waschromatographed by HPLC (elution agent: ethyl acetate: 60%; n-heptane40%). Yield: 53%. The product obtained was directly used in thesynthesis of the compound of formula (Ib) according to the methoddescribed in the first step of example 4.

EXAMPLE 6 para benzyloxyphenyl-3 N-methylaminomethyl-5 oxazolidinone-2(I) Code number: 81 First step: mesylate of parabenzyloxyphenyl-3hydroxymethyl-5 oxazolidinone-2 (XV)

To a solution of 28.5 g of para benzyloxyphenyl-3 hydroxymethyl-5oxazolidinone-2 (IId) in 27 ml of triethylamine and 750 ml of methylenechloride cooled to 5° C., were added 15 ml of mesyl chloride. They wereleft for 15 minutes in contact, then the solution was concentrated,diluted with water and the precipitate was filtered and recrystallizedin acetone. 32 g of product were obtained.

Yield: 90%

Melting point: 163° C.

Empirical formula: C₁₈ H₁₉ NO₆ S

Molecular weight: 377.41

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 57.28        5.07   3.71    Found (%)    57.30        4.95   3.46    ______________________________________

Second step: para benzyloxyphenyl-3 N-methylaminomethyl-5oxazolidinone-2 (I)

A mixture of 29 g of the compound obtained at the preceding step and 50g of ammonia in 500 ml of methanol, was heated to 110° C. for 6 hours inan autoclave. Then the solvent was evaporated, the residue was taken upin chloroform, washed with water, the solvent was evaporated and theresidue was recrystallized in isopropanol. 17 g of product wereisolated.

Yield: 74%

Melting point: 124° C.

Empirical formula: C₁₇ H₁₈ N₂ O₃

Molecular weight: 298.33

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 68.44        6.08   9.39    Found (%)    68.25        6.19   8.82    ______________________________________

By the same method, but from the corresponding reagents, the compoundsof formula (I) were prepared, given in table I and bearing the codenumbers: 74 to 86; 170 to 176 and 201 to 207.

EXAMPLE 7 N-parabenzyloxyphenyl-1 hydroxymethyl-4 pyrrolidinone-2 (XVII)First step: [(N-parabenzyloxyphenyl pyrrolidinone-2) yl-4]carboxylicacid (XIX)

A mixture of 46 g of itaconic acid and 70 g of parabenzyloxyaniline in400 ml of water was brought to reflux, then washed on the filter withchloroform, dried and recrystallized in acetone. 77 g of product wereobtained.

Yield: 71%

Melting point: 194° C.

Empirical formula: C₁₈ H₁₇ NO₄

Molecular weight: 311.32

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 69.44        5.50   4.50    Found (%)    69.69        5.48   4.80    ______________________________________

Second step: [(N-parabenzyloxyphenyl pyrrolidinone-2) yl-4]ethylcarboxylate (XVIII)

A solution of 84 g of the acid obtained in the first step in 400 ml ofethanol and 6 ml of concentrated sulfuric acid was brought to reflux for2 hours. Then, it was cooled, the precipitate was filtered, washed withwater, dried and recrytallized in isopropanol. 47 g of product wereobtained.

Yield: 51%

Melting point: 106° C.

Empirical formula: C₂₀ H₂₁ NO₄

Molecular weight: 339.38

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 70.78        6.24   4.13    Found (%)    70.96        6.39   4.44    ______________________________________

Third step: N-para benzyloxyphenyl-1 hydroxymethyl-4 pyrrolidinone-2(XVII)

To a mixture of 7.9 g of sodium borohydride and 18 g of lithium bromidein 400 ml of diglyme, were added 70 g of the compound prepared at thepreceding step. Then the mixture was brought to 100° C. in 50 mn,diluted in 500 g of ice and 50 ml of concentrated hydrochloric acid,extracted with chloroform; the solvent was evaporated, the residue wascrystallized in isopropyl ether and recrystallized in toluene. 45 g ofproduct were obtained.

Yield: 72%

Melting point: 110° C.

Empirical formula: C₁₈ H₁₉ NO₃

Molecular weight: 297.34

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 72.70        6.44   4.71    Found (%)    72.44        6.36   4.68    ______________________________________

EXAMPLE 8 N-parabenzyloxyphenyl hydroxymethyl-3 pyrrolidine (I) Codenumber: 220

A solution of 53 g of the compound of formula (XVIII) obtained inexample 7, in 300 ml of anhydrous tetrahydrofuran, was added whilecooling to 11.8 g of lithium aluminium hydride (pellets) in 1000 ml oftetrahydrofuran. Then it was brought to reflux for 2 hours, then 6.3 mlof water, 4.75 ml of 20% NaOH and 22 ml of water were successivelyadded. It was filtered, the filtrate was evaporated and the residue wascrystallized in ethyl acetate. 38 g of product were obtained.

Yield: 85%

Melting point: 87° C.

Empirical formula: C₁₈ H₂₁ NO₂

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 76.29        7.47   4.94    Found (%)    76.40        7.60   4.65    ______________________________________

EXAMPLE 9 para (metanitro) benzyloxyphenyl-3 methoxymethyl-5thiazolidinone-2(I) Code number: 219 First step: para (metanitro)benzyloxyanilino-3 methoxy-1 propane thiol-2, oxalate (XX)

To a solution of 48.8 g of para (metanitro) benzyloxyaniline in 700 mlof isopropanol were slightly added 20.8 g of methoxymethyl-2thiooxirane, and the mixture was brought to reflux for 7 hours. Then thesolvent was evaporated, and the residue was chromatographed on a silicacolumn. By eluting with methylene chloride, 38.4 g of an oil wereobtained which were dissolved in acetonitrile. A solution of oxalic acidwas added to acetonitrile, and the precipitate was filtered.

Yield: 43%

Melting point: 120° C.

Empirical formula: C₁₉ H₂₂ N₂ O₈ S

Molecular weight: 438.45

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 52.04        5.06   6.39    Found (%)    51.79        4.88   6.48    ______________________________________

Second step: para (metanitro) benzyloxyphenyl-3 methoxymethyl-5thiazolidinone-2 (I) Code number: 219

To a solution of 3 g of phosgene in 90 ml of dichloroethane, cooled to-10° C., was added 4.14 g of potassium carbonate then 6 g of thecompound of formula (XX) (base form) obtained in the previous step,dissolved in 50 ml of dichlorethane, while maintaining the temperaturebetween 5° and 10° C. Then, it came slowly to room temperature (3hours), water was added, the organic phase was decanted, dried on sodiumsulfate and the solvent was evaporated. The residue was crystallized inisopropyl ether, and recrystallized in isopropyl alcohol. 3 g of productwere obtained.

Yield: 47%

Melting point: 74° C.

Empirical formula: C₁₈ H₁₈ N₂ O₅ S

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 57.74        4.85   7.48    Found (%)    57.45        4.97   7.18    ______________________________________

EXAMPLE 10 para ethoxyphenyl-3 hydroxymethyl-5 oxazolidine thione-2 (I)Code number: 87

To a solution of 9.6 g of paraethoxyanilino-3 propanediol-1,2 (XXI) and20.5 ml of triethylamine in 100 ml of tetrahydrofuran, were slowly added5.2 g of thiophosgene while maintaining the temperature to 20° C. Thenafter 4 hours it was filtered, the filtrate was evaporated and theresidue chromatographed on a silica column. Eluted with chloroform, 5.3g of product were obtained.

Yield: 46%

Melting point: 133° C.

Empirical formula: C₁₂ H₁₅ NO₃ S

Molecular weight: 253.31

Elementary analysis:

    ______________________________________               C          H      N    ______________________________________    Calculated (%)                 56.89        5.97   5.53    Found (%)    56.98        6.14   5.54    ______________________________________

By the same method, but from the corresponding reagents, the compoundsof formula (I) were prepared, given in table I and bearing code numbers:88 to 98; 100, 101, 102, 113 to 120; 177 and 208 to 218.

    TABLE I      ##STR68##       Melting  ELEMENTARY ANALYSIS Code  Empirical Molecular point Yield     Calculated (%) Obtained (%) Number X A R.sub.1 R.sub.2 R formula weight     (°C.) (%) C H N C H N       1 Oxygen Oxygen H CH.sub.2 OCOCH.sub.3 4-OCH.sub.2CN C.sub.14 H.sub.14     N.sub.2 O.sub.5 290.27 92 72 57.93 4.86 9.65 57.90 4.87 9.42 2 " " "     CH.sub.2 OCOEt " C.sub.15 H.sub.16 N.sub.2 O.sub.5 304.29 66 81 59.20     5.30 9.21 59.11 5.37 9.06  3 " " " CH.sub.2      OCOCH.sub.3     ##STR69##       " " 68 75 59.20 5.30 9.21 59.03 5.25 9.35  4 " " " CH.sub.2 OCOEt "     C.sub.16 H.sub.18 N.sub.2 O.sub.5 318.32 66 80 60.37 5.70 8.80 60.44     5.54 8.64      5 " " "     ##STR70##      " C.sub.17 H.sub.20 N.sub.2 O.sub.5 332.34 72 58 61.43 6.07 8.43 61.14     6.23 8.37  6 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.18 H.sub.22     N.sub.2 O.sub.5 346.37 65 72 62.41 6.40 8.09 62.70 6.59 7.94  7 " " "      ##STR71##      " C.sub.18 H.sub.22 N.sub.2 O.sub.5 346.37 90 57 62.41 6.40 8.09 62.29     6.21 7.90      8 " " "     ##STR72##      " C.sub.20 H.sub.24 N.sub.2 O.sub.5 372.41 104  76 64.50 6.50 7.52     64.35 6.30 7.69  9 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.22     H.sub.30 N.sub.2 O.sub.5 402.48 75 75 65.65 7.51 6.96 65.41 7.35 6.72 10     " " "      ##STR73##      " C.sub.20 H.sub.18 N.sub.2 O.sub.5 366.36 150  68 65.56 4.95 7.65     65.27 4.82 7.55  11 " " " CH.sub.2 OCOCH.sub.3 4 OC.sub.4 H.sub.9n     C.sub.16 H.sub.21 NO.sub.5 307.34 60 92 62.52 6.89 4.56 62.49 6.90 4.55     12 " " "      ##STR74##      " C.sub.19 H.sub.27 NO.sub.5 349.41 82 30 65.31 7.79 4.01 65.04 7.72     3.81  13 " " " CH.sub.2      OCOCH.sub.3     ##STR75##      C.sub.18 H.sub.23 NO.sub.5 333.37 94 85 64.85 6.95 4.20 64.91 7.24 4.05      14 " " " CH.sub.2 OCOEt " C.sub.19 H.sub.25 NO.sub.5 347.39 90 82 65.69     7.25 4.03 65.76 7.20 4.35      15 " " "     ##STR76##      O "  C.sub.20 H.sub.27 NO.sub.5 361.42 78 54 66.46 7.53 3.88 66.21 7.51     3.66  16 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.21 H.sub.29 NO.sub.5     375.45 82 72 67.18 7.79 3.73 67.24 8.08 3.58      17 " " "     ##STR77##      " C.sub.21 H.sub.29 NO.sub.5 375.45 94 66 67.18 7.79 3.73 67.19 7.92     3.54      18 " " "     ##STR78##      " C.sub.23 H.sub.31 NO.sub.5 401.49 100  71 68.80 7.78 3.49 68.51 7.94     3.19  19 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.25 H.sub.37     NO.sub.5 431.55 78 62 69.57 8.64 3.25 69.76 8.91 3.10      20 " " "     ##STR79##      "  C.sub.23 H.sub.25 NO.sub.5 395.44 112  65 69.85 6.37 3.54 69.96 6.64     3.66  21 " " " CH.sub.2      OCOCH.sub.3     ##STR80##      C.sub.19 H.sub.25 NO.sub.5 347.39 102  72 65.69 7.25 4.03 65.96 7.55     3.98  22 " " " CH.sub.2 OCOEt " C.sub.20 H.sub.27 NO.sub.5 361.42 80 80     66.46 7.53 3.88 66.68 7.52 4.13  23 " " " CH.sub.2      OCOCH.sub.3     ##STR81##      C.sub.19 H.sub.19 NO.sub.5 341.35 120  76 66.85 5.61 4.10 67.07 5.54     3.86  24 " " " CH.sub.2 OCOEt " C.sub.20 H.sub.21 NO.sub.5 355.37 96 82     67.59 5.96 3.94 67.60 6.15 3.92      25 " " "     ##STR82##      " C.sub.21 H.sub.23 NO.sub.5 369.40 114  65 68.28 6.28 3.79 68.31 6.40     3.73  26 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.22 H.sub.25 NO.sub.5     383.43 86 71 68.91 6.57 3.65 69.02 6.55 3.60      27 " " "     ##STR83##      " C.sub. 22 H.sub.25 NO.sub.5 383.43 116  52 68.91 6.57 3.65 69.16 6.63     3.55  28 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.26 H.sub.33     NO.sub.5 439.53 95 60 71.04 7.57 3.19 70.97 7.52 2.90      29 " " "     ##STR84##      " C.sub.24 H.sub.21 NO.sub.5 403.42 128  69 71.45 5.25 3.47 71.26 5.08     3.15  30 " " " CH.sub.2      OCOCH.sub.3     ##STR85##      C.sub.19 H.sub.18 ClNO.sub.5 375.79 58 85 60.72 4.83 3.73 60.87 4.94     3.62  31 " " " CH.sub.2 OCOEt " C.sub.20 H.sub.20 ClNO.sub.5 389.82 82     82 61.62 5.17 3.59 61.64 5.45 3.59      32 " " "     ##STR86##      " C.sub.21 H.sub.22 ClNO.sub.5 403.85 88 62 62.45 5.49 3.47 62.30 5.46     3.20  33 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.22      H.sub.24 ClNO.sub.5 417.88 95 73 63.23 5.79 3.35 63.27 5.69 3.17  34 "     " "      ##STR87##      " " " 92 65 63.23 5.79 3.35 63.22 5.67 3.25  35 " " " CH.sub.2      OCOC.sub.8 H.sub.17n " C.sub.26 H.sub.32 ClNO.sub.5 473.98 74 65 65.88     6.81 2.96 66.11 7.05 3.22  36 " " " CH.sub.2      OCOCH.sub.3     ##STR88##      C.sub.19 H.sub.18 N.sub.2 O.sub.7 386.35 126  72 59.06 4.70 7.25 59.10     4.56 6.95  37 " " " CH.sub.2 OCOEt " C.sub.20 H.sub.20 N.sub.2 O.sub.7     400.38 106  75 59.99 5.03 7.00 59.86 5.03 6.71      38 " " "     ##STR89##      " C.sub.21 H.sub.22 N.sub.2 O.sub.7 414.40 108  58 60.86 5.35 6.76     60.62 5.45 6.49  39 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.22     H.sub.24 N.sub.2 O.sub.7 428.43 102  70 61.67 5.65 6.54 61.75 5.69 6.39     40 " " "      ##STR90##      " C.sub.22 H.sub.24 N.sub.2 O.sub.7 428.43 118  43 61.67 5.65 6.54     61.41 5.88 6.35      41 " " "     ##STR91##      " C.sub.24 H.sub.26 N.sub.2 O.sub.7 454.46 150  28 63.42 5.77 6.16     63.54 5.83 5.89  42 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.26     H.sub.32 N.sub.2 O.sub.7 484.53 83 65 64.45 6.66 5.78 64.18 6.82 5.64     43 " " "      ##STR92##      " C.sub.24 H.sub.20 N.sub.2 O.sub.7 448.42 182  60 64.28 4.50 6.25     64.39 4.39 6.17  44 " " " CH.sub.2      OCOEt     ##STR93##      C.sub.20 H.sub.20 FNO.sub.5 373.39 77 70 64.33 5.40 3.75 64.28 5.27     3.73  45 " " "  CH.sub.2 OCH.sub.3 3-CH.sub.3 C.sub.12 H.sub.15 NO.sub.3     221.25 58 71 65.14 6.83 6.33 65.36 6.66 6.01 46 " " " " 4 OC.sub.4     H.sub.9 n C.sub.15 H.sub.21 NO.sub.4 279.33 50 57 64.49 7.58 5.01 64.40     7.55 4.79      47 " " "     ##STR94##      " C.sub.17 H.sub.25 NO.sub.4 307.38 77 62 66.42 8.20 4.56 66.19 8.27     4.36      48 " " "     ##STR95##      " C.sub.20 H.sub.29 NO.sub.4 347.44 53 71 69.13 8.41 4.03 69.30 8.62     3.83  49 " " " CH.sub.2      OCH.sub.3     ##STR96##      C.sub.17 H.sub.23 NO.sub.4 305.36 70 48 66.86 7.59 4.59 66.79 7.47 4.44      50 " " "     ##STR97##      " C.sub.19 H.sub.27 NO.sub.4 333.41 66 35 68.44 8.16 4.20 68.54 8.39     4.22      51 " " "     ##STR98##      " C.sub.22 H.sub.31 NO.sub.4 373.47 67 59 70.75 8.37 3.75 70.63 8.53     3.85  52 " " " CH.sub.2      OCH.sub.3     ##STR99##      C.sub.14 H.sub.16 N.sub.2 O.sub.4 276.28 104  57 60.86 5.84 10.14 60.59     5.50 10.11      53 " " "     ##STR100##      " C.sub.16 H.sub.20 N.sub.2 O.sub.4 304.34 89 39 63.11 6.62 9.21 63.29     6.73 9.36      54 " " "     ##STR101##      " C.sub.19 H.sub.24 N.sub.2 O.sub.4 344.39 80 42 66.26 7.02 8.13 66.19     6.88 7.98  55 " " " CH.sub.2      OCH.sub.3     ##STR102##      C.sub.18 H.sub.25 NO.sub.4 319.39 90 63 67.69 7.89 4.39 67.96 7.83 4.39      56 " " " "     ##STR103##      C.sub.18 H.sub.23 NO.sub.4 317.37 80 55 68.12 7.30 4.41 68.21 7.61 4.39      57 " "  " "     ##STR104##      C.sub.18 H.sub.19 NO.sub.4 313.34 90 83 68.99 6.11 4.47 69.19 6.07 4.24      58 " " "     ##STR105##      " C.sub.20 H.sub.23 NO.sub.4 341.39 110  75 70.36 6.79 4.10 70.14 6.49     4.22  59 " " " CH.sub.2      OCH.sub.3     ##STR106##      C.sub.18 H.sub.18 ClNO.sub.4 347.79 96 78 62.16 5.22 4.03 61.99 5.11     3.88      60 " " "     ##STR107##      " C.sub.20 H.sub.22 ClNO.sub.4 375.84 99 70 63.91 5.90 3.73 63.92 5.90     3.68  61 " " " CH.sub.2      OCH.sub.3     ##STR108##      C.sub.18 H.sub.18 N.sub.2 O.sub.6 358.34 78 62 60.33 5.06 7.82 60.52     5.10 7.92      62 " " "     ##STR109##      " C.sub.20 H.sub.22 N.sub.2 O.sub.6 386.39 74 60 62.16 5.74 7.25 62.16     5.94 7.49      63 " " "     ##STR110##      " C.sub.23 H.sub.26 N.sub.2 O.sub.6 426.45 78 60 64.77 6.15 6.57 64.51     6.18 6.50  64 " " " CH.sub.2      OCH.sub.3     ##STR111##      C.sub.18 H.sub.18 FNO.sub.4 331.33 106  55 62.25 5.48 4.23 65.37 5.52     4.20      65 " " " "     ##STR112##      C.sub.19 H.sub.18 N.sub.2 O.sub.4 338.35 88 65 67.44 5.36 8.28 67.41     5.48 8.37      66 " " " "     ##STR113##      C.sub.19 H.sub.18 F.sub.3 NO.sub.4 381.34 83 60 59.84 4.76 3.67 59.81     4.62 3.70      67 " " " "     ##STR114##      C.sub.18 H.sub.18 FNO.sub.4 331.33 79 60 65.25 5.48 4.23 65.20 5.59     4.13      68 " " " "     ##STR115##      C.sub.18 H.sub.18 ClNO.sub.4 347.79 107  65 62.16 5.22 4.03 62.02 5.23     4.05  69 " " " CH.sub.2      OEt     ##STR116##      C.sub.19 H.sub.20 N.sub.2 O.sub.6 372.37 50 48 61.28 5.41 7.52 61.10     5.34 7.48  70 " " " CH.sub.2 OC.sub.3 H.sub.7n " C.sub.20 H.sub.22     N.sub.2 O.sub.6 386.39 52 75 62.16 5.74 7.25 62.09 5.63 7.06  71 " " "      ##STR117##      " C.sub.20 H.sub.20 N.sub.2 O.sub.6 384.38 <50  40 62.49 5.24 7.29     62.38 5.12 7.17      72 " " "     ##STR118##      " C.sub.20 H.sub.18 N.sub.2 O.sub.6 382.36 80 55 62.82 4.75 7.33 62.75     4.76 7.23      73 " " "     ##STR119##      " C.sub.19 H.sub.20 N.sub.2 O.sub.7 388.37 79 50 58.76 5.19 7.21 58.53     5.26 7.20  74 " " " CH.sub.2NHCH.sub.3 4 OC.sub.4 H.sub.9n C.sub.15     H.sub.22 N.sub.2 O.sub.3 278.34 56 75 64.72 7.97 10.07 64.57 7.81 10.18     75 " " "      ##STR120##      " C.sub.16 H.sub.24 N.sub.2 O.sub.3 292.37 68 70 65.73 8.27 9.58 65.73     8.01 9.49      76 " " " CH.sub.2NH.sub.2     ##STR121##      C.sub.16 H.sub.22 N.sub.2 O.sub.3 290.35 97 72 66.18 7.64 9.65 66.33     7.96 9.79  77 " " " CH.sub.2NHCH.sub.3 " C.sub.17 H.sub.24 N.sub.2     O.sub.3 304.38 71 70 67.08 7.95 9.20 66.85 7.96 9.14      78 " " "     ##STR122##      "  C.sub.18 H.sub.26 N.sub.2 O.sub.3 318.40 102  65 67.89 8.23 8.80     67.88 8.43 8.73      79 " " " CH.sub.2NHCH.sub.3     ##STR123##      C.sub.16 H.sub.24 N.sub.2 O.sub.3 292.37 67 62 65.73 8.27 9.58 65.44     8.23 9.73      80 " " " CH.sub.2NH.sub.2     ##STR124##      C.sub.17 H.sub.18 N.sub.2 O.sub.3 298.33 124  74 68.44 6.08 9.39 68.25     6.19 8.82  81 " " " CH.sub.2NHCH.sub.3 " C.sub.18 H.sub.20 N.sub.2     O.sub.3 312.36 88 71 69.21 6.45 8.97 69.51 6.36 8.42      82 " " " CH.sub.2NH.sub.2      ##STR125##      C.sub.17 H.sub.17 ClN.sub.2 O.sub.3 332.78 122  70 61.35 5.15 8.42     61.04 5.20 7.66  83 " " " CH.sub.2NHCH.sub.3 " C.sub.18 H.sub.19     ClN.sub.2 O.sub.3 346.81 72 55 62.33 5.52 8.08 61.93 5.35 8.35  84 " " "     CH.sub.2NH.sub.2      ##STR126##       C.sub.17 H.sub.17 N.sub.3 O.sub.5 343.33 88 50 59.47 4.99 12.24 59.21     4.71 12.54  85 " " " CH.sub.2NHCH.sub.3 " C.sub.18 H.sub.19 N.sub.3     O.sub.5 357.36 70 75 60.49 5.36 11.76 60.18 5.39 11.83  86 " " "      ##STR127##      " C.sub.19 H.sub.21 N.sub.3 O.sub.5 371.38 76 72 61.44 5.70 11.32 61.54     5.84 11.29  87 Sulfur " " CH.sub.2 OH 4-OEt C.sub.12 H.sub.15 NO.sub.3 S     253.31 133  46 56.89 5.97 5.53 56.98 6.14 5.54 88 " " " " 4 OC.sub.3     H.sub.7n C.sub.13 H.sub.17 NO.sub.3 S 267.34 84 42 58.40 6.41 5.24 58.55     6.59 5.25 89 " " " " 4 OC.sub.4 H.sub.9n C.sub.14 H.sub.19 NO.sub.3 S     281.37 95 55 59.76 6.81 4.98 59.64 6.80 4.86      90 " " " "     ##STR128##      C.sub.17 H.sub.23 NO.sub.3 S 321.43 100   40 63.52 7.21 4.36 63.27 7.01     4.15      91 " " " "     ##STR129##      C.sub.15 H.sub.21 NO.sub.3 S 295.39 80 40 60.99 7.17 4.74 60.75 7.10     4.74      92 " " " "     ##STR130##      C.sub.12 H.sub.11 N.sub.2 O.sub.3 S 263.29 96 35 54.74 4.21 10.64 54.49     4.64 10.70      93 " " " "     ##STR131##      C.sub.17 H.sub.16 ClNO.sub.3 S 349.83 132  40 58.36 4.61 4.00 58.17     4.61 4.00      94 " " " CH.sub.2OH     ##STR132##      C.sub.17 H.sub.16 N.sub.2 O.sub.3 S 360.38 142  37 56.65 4.48 7.77     56.36 4.29 7.58       95 " " " "     ##STR133##      C.sub.17 H.sub.16 ClNO.sub.3 S 349.83 163  42 58.36 4.61 4.00 58.31     4.55 3.98      96 " " " "     ##STR134##      C.sub.17 H.sub.16 FNO.sub.3 S 333.37 142  55 61.24 4.84 4.20 60.99 4.83     3.92      177 " " " "     ##STR135##      " " 153  37 61.24 4.84 4.20 60.94 4.78 4.10      97 " " " "     ##STR136##      C.sub.18 H.sub.16 N.sub.2 O.sub.3 S 340.39 162  40 63.51 4.74 8.23     63.30 5.00 8.08      98 " " " "     ##STR137##      C.sub.18 H.sub.16 F.sub.3 NO.sub.3 S 383.38 95 52 56.39 4.21 3.65 56.08     4.14 3.30      99 Oxygen CH.sub.2 " "     ##STR138##      C.sub.18 H.sub.18 N.sub.2 O.sub.5 342.34 96 85 63.15 5.30 8.18 62.98     5.31 7.96      100 Sulfur Oxygen " "     ##STR139##      C.sub.16 H.sub.21 NO.sub.3 S 307.40 63 40 62.51 6.89 4.56 62.33 6.90     4.56      101 " " " "     ##STR140##      C.sub.17 H.sub.21 NO.sub.3 S 319.41 112  35 63.92 6.63 4.39 63.64 6.76     4.17      102 " " " "     ##STR141##      C.sub.13 H.sub.14 N.sub.2 O.sub.3 S 278.32 108  43 56.10 5.07 10.07     55.80 5.05 9.87      103 Oxygen " "     ##STR142##      ##STR143##      C.sub.21 H.sub.29 NO.sub.5 375.45 98 76 67.18 7.79 3.73 67.45 7.87 3.97      104 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.22 H.sub.31 NO.sub.5     389.47 96 76 67.84 8.02 3.60 67.91 8.01 3.54      105 " " "     ##STR144##      " C.sub.22 H.sub.31 NO.sub.5 389.47 120  73 67.84 8.02 3.60 67.86 8.10     3.45  106 " " " CH.sub.2      OCOEt     ##STR145##      C.sub.20 H.sub.20 FNO.sub.5 373.37 77 80 64.33 5.40 8.75 64.28 5.27     3.73      107 " " "     ##STR146##      " C.sub.21 H.sub.22 FNO.sub.5 387.39 87 62 65.10 5.72 3.62 65.19 5.78     3.60  108 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.22 H.sub.24     FNO.sub.5 401.42 92 71 65.82 6.03 3.49 65.83 5.86 3.42 109 " " "     CH.sub.2 OEt 4-OC.sub.4 H.sub.9 n C.sub.16 H.sub.23 NO.sub.4 293.35 64     32 65.50 7.90 4.78 65.63 8.08 4.67  110 " " " CH.sub.2 OCH.sub.3      ##STR147##      C.sub.15 H.sub.18 N.sub.2 O.sub.4 290.31 54 68 62.05 6.25 9.65 62.07     6.42 9.61      111 " " " "     ##STR148##      C.sub.16 H.sub.23 NO.sub.4 293.35 50 65 65.50 7.90 4.78 65.52 8.03 4.71      112 O O " " 4-O(CH.sub.2).sub.4CN C.sub.16 H.sub.20 N.sub.2 O.sub.4     304.34 78 50 63.14 6.62 9.21 63.00 6.45 9.09  113 Sulfur Oxygen "     CH.sub.2      OH     ##STR149##      C.sub.17 H.sub.15 NClO.sub.5 S 394.83 144  58 51.71 3.83 7.10 51.87     3.87 7.34  114 " " " CH.sub.2      OCH.sub.3     ##STR150##      C.sub.18 H.sub.25 NO.sub.3 S 335.45 102  76 64.44 7.51 4.18 64.35 7.46     4.12  115 " " " CH.sub.2 OCOCH.sub.3 " C.sub.19 H.sub.25 NO.sub.4 S     363.46 96 52 62.78 6.93 3.85 62.64 7.00 3.85  116 " " " CH.sub.2     OCH.sub.3      ##STR151##      C.sub.19 H.sub.18 N.sub.2 O.sub.3 S 354.42 108  61 64.38 5.12 7.90     64.37 4.82 7.76  117 " " " CH.sub.2      OCOCH.sub.3     ##STR152##      C.sub.19 H.sub.18 N.sub.2 O.sub.6 S 402.42 104  71 56.71 4.51 6.96     56.91 4.28 6.73  118 " " " CH.sub.2 OCH.sub.3 " C.sub.18 H.sub.18     N.sub.2 O.sub.5 S 374.41 97 67 57.74 4.85 7.48 57.60 4.77 7.40  119 " "     " CH.sub.2      OH     ##STR153##      C.sub.16 H.sub.21 NO.sub.4 S 323.40 117  58 59.42 6.55 4.33 59.17 6.62     4.26  120 " " " CH.sub.2      OCOCH.sub.3     ##STR154##      C.sub.20 H.sub.18 N.sub.2 O.sub.4 S 382.43 99 82 62.81 4.74 7.33 62.88     4.67 7.33      121 Oxygen " "     ##STR155##      ##STR156##      C.sub.24 H.sub.33 NO.sub.5 415.51 128  87 69.37 8.01 3.37 69.33 7.99     3.29  122 " " " CH.sub.2 OCOC.sub.8      H.sub.17n     ##STR157##      C.sub.26 H.sub.39 NO.sub. 5 445.58 82 78 70.08 8.82 3.14 70.01 8.67     3.06  123 " " " CH.sub.2      OCOCH.sub.3     ##STR158##      C.sub.17 H.sub.23 NO.sub.5 321.36 80 60 63.53 7.21 4.36 63.66 7.36 4.39      124 " " " CH.sub.2 OCOEt " C.sub.18 H.sub.25 NO.sub.5 335.39 78 60     64.46 7.51 4.18 64.35 6.96 4.25      125 " " "     ##STR159##      " C.sub.20 H.sub.29 NO.sub.5 363.24 75 74 66.09 8.04 3.85 65.91 7.73     3.80  126 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.24 H.sub.37     NO.sub.5 419.54 67 72 68.70 8.89 3.34 68.41 8.93 3.19  127 " " "      ##STR160##      ##STR161##      C.sub.19 H.sub.27 NO.sub.5 349.41 64 76 65.31 7.79 4.01 65.24 7.88 3.98      128 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.20 H.sub.29 NO.sub.5     363.44 70 64 66.09 8.04 3.85 65.96 7.85 3.70      129 " " "     ##STR162##      " C.sub.22 H.sub.31 NO.sub.5 389.48 81 68 67.84 8.02 3.60 67.66 8.03     3.71  130 " " " CH.sub.2      OCOCH.sub.3     ##STR163##      C.sub.19 H.sub.18 FNO.sub.5 359.34 60 65 63.50 5.04 3.89 63.28 5.14     3.70  131 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.26 H.sub.32     FNO.sub.5 457.52 73 73 68.24 7.05 3.06 68.30 6.96 3.16  132 " " "     CH.sub.2      OCOEt     ##STR164##      C.sub.21 H.sub.20 N.sub.2 O.sub.5 380.39 90 78 66.30 5.30 7.36 66.31     5.52 7.24  138 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.27 H.sub.32     N.sub.2 O.sub.5 464.54 72 77 69.80 6.94 6.03 69.63 7.15 5.91  134 " " "      ##STR165##      ##STR166##      C.sub.22 H.sub.24 N.sub.2 O.sub.7 428.43 84 40 61.67 5.65 6.54 61.31     5.50 6.28  135 " " " CH.sub.2      OCOEt     ##STR167##      C.sub.20 H.sub.20 FNO.sub.5 373.37 87 81 64.33 5.40 3.75 64.51 5.12     3.70  136 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.26 H.sub.32     FNO.sub.5 457.52 94 83 68.25 7.05 3.06 68.54 6.82 2.97  137 " " "     CH.sub.2      OCOEt     ##STR168##      C.sub.20 H.sub.19 ClN.sub.2 O.sub.7 434.82 104  73 55.24 4.40 6.44     54.93 4.11 6.35  138 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.26     H.sub.31 ClN.sub.2 O.sub.7 518.99 102  87 60.17 6.02 5.40 60.02 5.82     5.35  139 " " " CH.sub.2 OCOC.sub.8      H.sub.17n     ##STR169##      C.sub.27 H.sub.31 N.sub.3 O.sub.7 509.54 100  70 63.64 6.13 8.25 63.51     5.99 8.24  140 " " " CH.sub.2 OCOEt " C.sub.21 H.sub.19 N.sub.3 O.sub.7     425.39 145  50 59.29 4.50 9.88 58.67 4.33 9.78  141 " " " CH.sub.2     OCOCH.sub.2      OCH.sub.3     ##STR170##      C.sub.20 H.sub.20 N.sub.2 O.sub.8 416.38 125  55 57.69 4.84 6.73 57.63     4.78 6.58  142 " " " CH.sub.2 OC.sub.3 H.sub.7n 4 OC.sub.4 H.sub.9n     C.sub.17 H.sub.25 NO.sub.4 307.38 72 52 66.42 8.20 4.56 66.35 8.39 4.72     143 " " " "      ##STR171##      C.sub.19 H.sub.27 NO.sub.4 333.41 72 63 68.44 8.16 4.20 68.20 7.89 4.11      144 " " " CH.sub.2      OCH.sub.3     ##STR172##      C.sub.17 H.sub.23 NO.sub.5 321.36 100  81 63.53 7.21 4.36 63.36 7.09     4.27  145 " " " CH.sub.2 OC.sub.3      H.sub.7     ##STR173##      C.sub.16 H.sub.20 N.sub.2 O.sub.4 304.34 40 38 63.14 6.62 9.21 62.96     6.31 8.96  146 " " " CH.sub.2      OEt     ##STR174##      C.sub.18 H.sub.25 NO.sub.4 319.39 82 79 67.69 7.89 4.39 67.44 7.95 4.36      147 " " " "     ##STR175##      C.sub.15 H.sub.18 N.sub.2 O.sub.4 290.31 77 41 62.05 6.25 9.65 62.15     5.97 9.61  148 " " " CH.sub.2 OCH.sub.3 4 OC.sub.5 H.sub.11n C.sub.16     H.sub.23 NO.sub.4 293.35 58 82 65.50 7.90 4.78 65.45 7.91 4.68 149 " " "     " 4 OC.sub.6 H.sub.13n C.sub.17 H.sub.25 NO.sub.4 307.38 ≦50  76     66.42 8.20 4.56 66.43 8.12 4.44      150 " " " "     ##STR176##      C.sub.19 H.sub.27 NO.sub.4 333.41 71 32 68.44 8.16 4.20 68.39 8.17 4.37      151 " " " "     ##STR177##      C.sub.14 H.sub.17 NO.sub.5 279.28 58 85 60.20 6.14 5.02 59.94 6.02 5.11      152 " " " CH.sub.2 OC.sub.3      H.sub.7n     ##STR178##      C.sub.20 H.sub.23 NO.sub.4 341.39 105  67 70.36 6.79 4.10 70.17 6.80     3.86      153 " " " "     ##STR179##      C.sub.20 H.sub.22 ClNO.sub.4 375.84 75 71 63.91 5.90 3.73 63.95 6.07     3.93  154 " " " CH.sub.2      OEt     ##STR180##      C.sub.19 H.sub.21 NO.sub.4 327.37 105  85 69.70 6.47 4.28 69.44 6.48     4.23      155 " " " "     ##STR181##      C.sub.19 H.sub.20 ClNO.sub.4 361.81 81 82 63.07 5.57 3.87 62.89 5.38     3.80  156 " " " CH.sub.2      OCH.sub.3     ##STR182##      C.sub.18 H.sub.17 ClN.sub.2 O.sub.6 392.79 110  64 55.04 4.36 7.13     54.98 4.35 7.17      157 " " "     ##STR183##      ##STR184##      C.sub.21 H.sub.24 N.sub.2 O.sub.6 400.42 76 62 62.99 6.04 7.00 62.68     5.79 6.85      158 " " "     ##STR185##      " C.sub.22 H.sub.26 N.sub.2 O.sub.6 414.44 70 59 63.75 6.32 6.76 63.49     6.11 6.62  159 " " " CH.sub.2      OCH.sub.3     ##STR186##      C.sub.19 H.sub.18 N.sub.2 O.sub.4 338.35 110  78 67.44 5.36 8.28 67.21     5.06 8.20  160 " " " CH.sub.2 OC.sub.3      H.sub.7n     ##STR187##      C.sub.21 H.sub.22 N.sub.2 O.sub.4 366.40 75 60 68.83 6.05 7.65 68.51     5.98 7.67   161 " " " CH.sub.2      OCH.sub.3     ##STR188##      C.sub.19 H.sub.17 N.sub.3 O.sub.6 383.35 163  52 59.63 4.47 10.96 59.50     4.60 10.85  162 " " " CH.sub.2      OCH.sub.3     ##STR189##      C.sub.19 H.sub.17 FN.sub.2 O.sub.4 356.34 93 58 64.04 4.81 7.86 63.78     4.80 7.71 163 " " " "      ##STR190##      C.sub.18 H.sub.17 ClFNO.sub.4 365.78 90 34 59.10 4.68 3.83 59.40 4.55     4.07      164 " " " "     ##STR191##      C.sub.18 H.sub.17 Cl.sub.2 NO.sub.4 382.24 93 83 56.56 4.48 3.66 56.45     4.23 3.66      165 " " " "     ##STR192##      C.sub.18 H.sub.18 N.sub.2 O.sub.6 358.34 134   75 60.33 5.06 7.82 60.08     4.74 7.55      166 " " " "     ##STR193##      C.sub.18 H.sub.17 Cl.sub.2 NO.sub.4 382.24 76 69 56.56 4.48 3.66 56.47     4.46 3.73  167 " " " CH.sub.2      OEt     ##STR194##      C.sub.20 H.sub.20 N.sub.2 O.sub.4 352.38 ≦50  57 68.17 5.72 7.95     67.93 5.50 8.04  168 " " " CH.sub.2      OCH.sub.3     ##STR195##      C.sub.18 H.sub.17 ClN.sub.2 O.sub.6 392.79 94 67 55.04 4.36 7.13 55.04     4.25 7.40      169 " " " "     ##STR196##      C.sub.18 H.sub.17 FN.sub.2 O.sub.6 376.33 95 61 57.44 4.55 7.44 57.30     4.56 7.29  170 " " " CH.sub.2 NH.sub.2 4 OC.sub.4 H.sub.9n C.sub.14     H.sub.20 N.sub.2 O.sub. 3 264.32 90 26 63.61 7.63 10.60 63.31 7.47 10.60      171 " " "     ##STR197##      ##STR198##      C.sub.15 H.sub.19 N.sub.3 O.sub.3 289.33 97 17 62.26 6.62 14.52 62.43     6.52 14.46  172 " " " CH.sub.2      NH.sub.2     ##STR199##      C.sub.17 H.sub.24 N.sub.2 O.sub.3 304.38 98 43 67.08 7.95 9.20 67.15     7.87 8.92  173 " " " CH.sub.2 NHCH.sub.3 " C.sub.18 H.sub.26 N.sub.2     O.sub.3 318.40 96 32 67.89 8.23 8.30 68.29 8.17 3.30  174 " " " CH.sub.2     NH.sub.2      ##STR200##      C.sub.15 H.sub.22 N.sub.2 O.sub.3 278.34 84 45 64.72 7.97 10.07 64.80     7.91 10.16  175 " " " CH.sub.2      NHCH.sub.3     ##STR201##      C.sub.18 H.sub.19 N.sub.2 O.sub.3 F 330.35 85 36 65.44 5.80 8.48 65.45     5.82 8.34   176 " " " CH.sub.2 NH.sub.2 " C.sub.17 H.sub.17 N.sub.2     O.sub.2 F 316.32 129  29 44.54 5.42 8.86 64.29 5.46 8.65  178 O O "      ##STR202##      ##STR203##      C.sub.25 H.sub.22 N.sub.2 O.sub.8 478.44 120  64 62.76 4.64 5.86 62.89     4.66 5.84  179 " " " CH.sub.2      OCH.sub.3     ##STR204##      C.sub.15 H.sub.19 NO.sub.4 277.31 63 74 64.96 6.91 5.05 64.67 6.77 4.97      180 " " " "     ##STR205##      C.sub.13 H.sub.18 N.sub.2 O.sub.3 250.29 92 59 62.38 7.25 11.19 62.45     6.98 10.94      181 " " " "     ##STR206##      C.sub.17 H.sub.24 N.sub.2 O.sub.5 336.38 92 75 60.70 7.19 8.33 60.47     7.04 8.10      182 " " " "     ##STR207##      C.sub.17 H.sub.23 NO.sub.5 321.36 77 22 63.53 7.21 4.36 63.67 7.23 4.38      183 " " " "     ##STR208##      C.sub.16 H.sub.21 NO.sub.4 291.34 81 31 65.96 7.27 4.81 66.00 7.46 4.71      184 " " " "     ##STR209##      C.sub.17 H.sub.21 NO.sub.4 303.35 83 33 67.31 6.98 4.62 67.01 7.08 4.43      185 " " " "     ##STR210##      C.sub.16 H.sub.21 NO.sub.4 291.34 84 78 65.96 7.27 4.81 66.03 7.28 4.59      234 " " " " 4 O(CH.sub.2).sub.4 Cl C.sub.15 H.sub.20 ClNO.sub.4 313.77     58 66 57.41 6.42 4.46 57.05 6.50 4.50      186 " " " "     ##STR211##      C.sub.18 H.sub.25 NO.sub.4 319.39 77 22 67.69 7.89 9.39 67.62 8.03 4.25      187 " " " "     ##STR212##      C.sub.19 H.sub.19 NO.sub.3 309.35 166  26 73.76 6.19 4.53 73.52 6.10     4.38      188 " " " "     ##STR213##      C.sub.18 H.sub.23 NO.sub.5 333.37 102  70 64.85 6.95 4.20 64.82 7.11     4.19      189 " " " "     ##STR214##      C.sub.19 H.sub.17 NO.sub.3 307.33 120  50 74.25 5.58 4.56 74.18 5.30     4.47      190 " " " "     ##STR215##      C.sub.19 H.sub.18 NO.sub.3 Cl 343.80 136  30 66.37 5.28 4.07 66.08 5.24     3.90      191 " " " "     ##STR216##      C.sub.19 H.sub.18 N.sub.2 O.sub.5 354.35 110  50 64.40 5.12 7.91 64.17     5.24 7.96      192 " " " "     ##STR217##      C.sub.19 H.sub.21 NO.sub.3 311.37 74 62 73.29 6.80 4.50 73.17 6.93 4.53      193 " " " "     ##STR218##      C.sub.19 H.sub.19 NO.sub.3 309.35 82 60 73.16 6.19 4.63 73.47 6.10 4.50      194 " " " "     ##STR219##      C.sub.19 H.sub.18 N.sub.2 O.sub.5 354.35 Oil 40 64.40 5.12 7.91 64.25     5.27 7.92      195 " " " "     ##STR220##      C.sub.17 H.sub.17 NO.sub.3 283.31 120  75 72.06 6.05 4.94 72.27 5.91     4.62      196 " " " "     ##STR221##      C.sub.20 H.sub.18 N.sub.2 O.sub.3 334.36 127  70 71.84 5.43 8.38 71.89     5.36 8.45      197 "  " " "     ##STR222##      C.sub.18 H.sub.18 BrNO.sub.4 392.24 116  81 55.11 4.63 3.57 54.94 4.35     3.55      198 " " " "     ##STR223##      C.sub.18 H.sub.18 NIO.sub.4 439.24 118  78 49.22 4.13 3.19 49.39 4.08     3.13      199 " " " "     ##STR224##      C.sub.19 H.sub.18 N.sub.2 O.sub.4[α].sub.D.sup.20 = -39°7     338.35(C = 1/CH.sub.2 Cl.sub.2) 83 75 67.44 5.36 8.28 67.14 5.53 8.38     200 " " " "      ##STR225##      C.sub.19 H.sub.18 N.sub.2 O.sub.4[α].sub.D.sup.20 = +32°1     338.35(C = 1/CH.sub.2 Cl.sub.2) 84 51 67.44 5.36 8.28 67.52 5.36 8.28     201 " " "      ##STR226##      ##STR227##      C.sub.20 H.sub.23 N.sub.3 O.sub.5 385.41 76 36 62.32 6.02 10.90 62.04     5.90 10.75      202 " " "     ##STR228##      " C.sub.21 H.sub.23 N.sub.3 O.sub.6 413.42 138  26 61.01 5.61 10.17     61.11 5.67 10.01  203 " " " CH.sub.2NHEt " C.sub.19 H.sub.21 N.sub.3     O.sub.5 371.38 70 54 61.44 5.70 11.32 61.48 5.58 11.57  204 " " "      ##STR229##      " C.sub.21 H.sub.23 N.sub.3 O.sub.5 397.42 110  24 63.46 5.83 10.57     63.16 5.90 10.39      205 " " " CH.sub.2NH.sub.2     ##STR230##      C.sub.18 H.sub.17 N.sub.3 O.sub.3 323.34 94 10 66.86 5.30 13.00 66.73     5.58 12.69      206 " " "     ##STR231##      " C.sub.20 H.sub.21 N.sub.3 O.sub.3 351.39 84 62 68.36 6.02 11.96 68.38     6.30 11.68 207 " " " CH.sub.2NH.sub.2      ##STR232##      C.sub.17 H.sub.16 ClN.sub.3 O.sub.5 475.06 155  11 54.04 4.27 11.12     54.17 4.31 11.26  208 S " " CH.sub.2      OCOEt     ##STR233##      C.sub.20 H.sub.20 N.sub.2 O.sub.6 S 416.44 126  73 57.68 4.84 6.73     57.59 5.03 6.69  209 " " " CH.sub.2      OH     ##STR234##      C.sub.18 H.sub.15 FN.sub.2 O.sub.3 S 358.38 126  27 59.57 4.31 7.72     59.72 4.52 7.54  210 " " " CH.sub.2      OC.sub.3 H.sub.7n     ##STR235##      C.sub.20 H.sub.22 N.sub.2 O.sub.5 S 402.46 110  57 59.68 5.51 6.96     59.57 5.65 7.19  211 " " " CH.sub.2      OCH.sub.3     ##STR236##      C.sub.17 H.sub.23 NO.sub.3 S 321.43 68 35 63.52 7.21 4.36 63.61 7.43     4.33  212 " " " CH.sub.2 OH 4 O(CH.sub.2).sub.3CN C.sub.14 H.sub.16     N.sub.2 O.sub.3 S 292.35 80 54 57.51 5.52 9.58 57.40 5.32 9.42  213 " "     " CH.sub.2      OCH.sub.3     ##STR237##      C.sub.17 H.sub.18 N.sub.2 O.sub.3 S 460.95 133  17 51.85 4.57 6.08     51.68 4.40 6.04      214 " " " "     ##STR238##      C.sub.16 H.sub.33 NO.sub.3 S 309.42 Oil 30 62.10 7.49 4.53 62.41 7.61     4.45  215 " " " CH.sub.2 OH 4 O(CH.sub.2).sub.4CN C.sub. 15 H.sub.18     N.sub.2 O.sub.3 S 306.37 106  40 58.80 5.92 9.14 58.88 5.74 9.12  216 "     " " CH.sub.2      OEt     ##STR239##      C.sub.19 H.sub.20 N.sub.2 O.sub.5 S 388.43 80 47 58.75 5.19 7.21 58.68     5.09 7.28  217 " " " CH.sub.2 OCH.sub.3 4 O(CH.sub.2).sub.4CN C.sub.16     H.sub.20 N.sub.2 O.sub.3 S 320.40 Oil 24 59.97 6.29 8.74 59.81 6.28 9.02      218 " " " "     ##STR240##      C.sub.19 H.sub.17 N.sub.3 O.sub.5 S 399.42 176  57 57.13 4.29 10.52     57.06 4.19 10.46      219 O S " "     ##STR241##      C.sub.18 H.sub.18 N.sub.2 O.sub.5 S 374.41 74 47 57.74 4.85 7.48 57.45     4.97 7.18  220 H.sub.2 CH.sub.2 " CH.sub.2      OH     ##STR242##      C.sub.18 H.sub.21 NO.sub.2 283.36 87 85 76.29 7.47 4.94 76.40 7.60     4.65

                                      TABLE II    __________________________________________________________________________     ##STR243##                                        (IX)    Code                     Molecular                                   Melting Point                                          Yield                                              Elementary Analysis    Number         R.sub.6   Empirical Formula                             Weight                                   (°C.)                                          %   %  C  H  N    __________________________________________________________________________    226  C.sub.3 H.sub.7n                   C.sub.20 H.sub.23 NO.sub.4                             341.39                                   105    62  Cal.                                                 70.36                                                    6.79                                                       4.10                                              Obt.                                                 70.17                                                    6.80                                                       3.86    227  Et        C.sub.19 H.sub.21 NO.sub.4                             327.37                                   105    58  Cal.                                                 69.70                                                    6.47                                                       4.28                                              Obt.                                                 69.44                                                    6.48                                                       4.23     228          ##STR244##                   C.sub.21 H.sub.25 NO.sub.4                             355.42                                   107    61  Cal. Obt.                                                 70.96 71.09                                                    7.09 6.77                                                       3.94 3.70     229          ##STR245##                   C.sub. 22 H.sub.27 NO.sub.4                             369.44                                   101    61  Cal. Obt.                                                 71.52 71.71                                                    7.37 7.41                                                       3.79 3.83    __________________________________________________________________________

                                      TABLE III    __________________________________________________________________________     ##STR246##                                                (VIII)                                         Melting Point                                                Yield                                                    ELEMENTARY ANALYSIS    Code Number            R'.sub.6  Empirical Formula                                Molecular Weight                                         (°C.)                                                (%)     C   H   N    __________________________________________________________________________    221             ##STR247##                      C.sub.13 H.sub.17 NO.sub.4                                251.27   93     70  Cal. Obt.                                                        62.14 62.14                                                            6.82 6.80                                                                5.57 5.56     222    CH.sub.3  C.sub.11 H.sub.13 NO.sub.4                                223.22   106    81  Cal.                                                        59.18                                                            5.87                                                                6.28                                                    Obt.                                                        59.15                                                            6.01                                                                6.38     223             ##STR248##                      C.sub.16 H.sub.21 NO.sub.4                                291.34   108    92  Cal. Obt.                                                        65.96 66.17                                                            7.27 7.58                                                                4.81 5.01     224    C.sub.3 H.sub.7n                      C.sub.13 H.sub.17 NO.sub.4                                251.27   88     78  Cal.                                                        62.14                                                            6.82                                                                5.57                                                    Obt.                                                        62.16                                                            6.53                                                                5.60    __________________________________________________________________________     ##STR249##                                                (VIII)                                         Melting Point                                                Yield                                                    ELEMENTARY ANALYSIS    Code Number            R'.sub.6  Empirical Formula                                Molecular Weight                                         (°C.)                                                %   %   C   H   N    __________________________________________________________________________    230     Et        C.sub.12 H.sub.15 NO.sub.4                                237.25   86     81  Cal.                                                        60.75                                                            6.37                                                                5.90                                                    Obt.                                                        60.60                                                            6.21                                                                5.83     231             ##STR250##                      C.sub.14 H.sub.19 NO.sub.4                                265.30   98     85  Cal. Obt.                                                        63.38 63.28                                                            7.22 7.04                                                                5.28 5.39     232             ##STR251##                      C.sub.15 H.sub.21 NO.sub.4                                279.33   80     82  Cal. Obt.                                                        64.49 64.30                                                            7.58 7.42                                                                5.01 4.84    __________________________________________________________________________

The compounds of formula (I) were studied on laboratory animals andshowed activities in the psychotropic field, as potentialanti-depressants.

These activities were revealed in the following tests:

Test A: Potentiation in mice of generalized trembling caused by aninterperitoneal injection (200 mg/kg) of dl-5-hydroxytryptophane,following the protocol described by C. GOURET and G. RAYNAUD in J.Pharmacol. (Paris), (1974), 5, 231.

Test B: Antagonism with respect to the ptosis observed one hour after anintravenous injection (2 mg/kg) of reserpine given to mice, followingthe protocol described by C. GOURET and J. THOMAS in J. Pharmacol.(Paris), 1973, 4, 401.

The results of these two tests, as well as those of a well-knowreference substance, TOLOXATONE, are collected in table IV below:

                  TABLE IV    ______________________________________    Com-    pound    tested    Code                            Toxicity    Num-  Test A       Test B       LD/50    ber   ED/50/mg/kg/po                       ED/50/mg/kg/po                                    Mouse/mg/kg/po    ______________________________________    1     12.5         6.2    2     12.5         8    3     3.1          2.7          >2000    4     2.3          3.4    5     4.7          9.5    6     2.4          6    7     --           7.4    8     2.2          7.2    9     --           25    10    2.4          5.8    11    4.2          6.2    12    4.6          6    13    3            2            >2000    14    2            3.1    15    2.2          2    16    1.7          1.5    17    4.8          3.6    18    4            4.25    19    5.5          3.5    20    8.8          3.7    21    2.1          3.5    22    --           3    23    12           12.5    24    9            12.5         >2000    25    15           25    26    12.5         20    27    25           44    28    32           20    29    45           50    30    4.2          4.5    31    6.5          3.6    32    4.7          3.6    33    9.4          4.5    34    7            7.5    35    19           6.5    36    1.7          1.5    37    1.9          2    38    1.5          2    39    1.75         1.6    40    6.2          1.5    41    6.2          4.5    42    1.25         2    43    15           17.5    44    6.2          --    45    45           50    46    1.5          2    47    18           36    48    50           50    49    0.5          0.4           2000    50    17.5         15    51    27           50    52    1.2          --           >2000    53    5            5.8    54    14           12.5    55    0.6          1.1    56    --           3    57    7.8          9    58    50           8.8    59    3.4          3.1    60    30           --    61    0.08         0.1           1500    62    3.6          2.4    63    9.4          16.5    64    --           4.5    65    0.28         0.75    66    4.7          6    67    4.4          5.6    68    5            6.2    69    0.5          0.2    70    0.8          0.6    71    1            0.8    72    0.8          1    73    0.6          0.8    74    4            6.2    75    8            --    76    2.1          6.2    77    2.5          6.2          >2000    78    6.2          --    79    6.2          2    80    20           25    81    24           25    82    9.6          12    83    12.5         6.2    84    3            1.3    85    3            2             1000    86    4.5          4.8    87    29           44    88    12.5         33    89    12.5         12.5    90    3            8    91    4.5          5.5          >2000    92    30           50    93    9            6    94    1.5          1            >2000    95    50           35    96    4.7          3.6    177   8            15.5    97    3.9          3.2    98    12.5         12.5    99    50           30           >2000    111   0.28         --    100   6.2          --    101   18           --    102   6.2          --    103   5            6    104   6.2          --    105   6.2          --    106   6.2          --    107   --           12    108   5.6          --    109   0            1    110   0.3          --    112   0.1          0.15    TOL-  60           50    OXA-    TONE    114   3.7          2            >2000    115   3.8          4.8    116   1.6          0.95    117   1.2          1.5    118   1            0.1          >2000    119   --           8    120   --           3    121   11           8    122   6.8          6.2    123   2            1.4          >2000    124   --           0.6    125   5            3.5    126   4.4          1.8    127   5            4.3    128   7.2          4.8    129   7.5          12    130   6.2          9.6    131   12           31    132   3            2            >2000    133   6            5.2    134   --           3.9    135   --           4.2    136   --           31    137   --           6    138   --           6    142   18           17.5    143   12.5         12    144   2.2          1.1    145   8.5          12    146   5            12.5    147   1.5          2.6    148   2.2          --    149   6            --    152   18           15.5    153   3.8          4    ______________________________________    Com-    pound    tested    Code  Test A       Test B       Toxicity    num-  ED.sub.50    ED.sub.50    LD.sub.50 Mouse    ber   (mg/kg/po)   (mg/kg/po)   (mg/kg/po)    ______________________________________    154   19           17.5    155   9.6          3    156   0.47         0.3    157   4.7          6.2    158   6            6    159   5.2          4.8    160   --           4.2    161   1.1          0.36         >2000    162   0.54         1.55    163   1.15         8    170   12.5         16    171   19.5         25    172   --           8.6    173   --           4.7    175   5.8          9.6    176   4            4    150   0.7          0.5    151   5.2          5    164   3.4          3.4    165   6.8          4.7    166   3.8          3.4    167   3.7          3    168   25           16           >1000    169   3            4.1          >1000    174   3            3.5    113   3.2          3.5    178   33           28           >1000    179   4.5          7            >1000    180   7.4          7.8           1000 (20%)    181   4            9            >1000    182   3.7          5.8          >1000    183   1.9          2.4          >1000    184   1.2          0.72         >1000    185   12           7            >1000    186   3            3            >1000    187   2.7          1.3          >1000    188   0.3          0.4           --    189   2.6          0.9          >1000    190   1            0.23         >1000    191   0.4          0.38          1000 (40%)    192   5.8          6            >1000    193   19           30            --    194   6.4          5.8           --    195   1.2          2.2          >1000    196   --           0.55         >1000    197   2.2          6.7          >1000    198   40           34           >1000    199   0.31         --           >1000    200   1.7          --           >1000    201   7.4          6.8          >1000    202   10           10           >1000    203   5.2          1.4           1000 (40%)    204   50           40            1000 (40%)    205   10.1         3            >1000    206   6            4.3          >1000    207   9.1          7.6          >1000    208   10           4.2          >1000    209   7            6.7           1000 (20%)    210   26           7.4          >1000    211   2            1.2           1000 (20%)    212   4.3          12            1000 (40%)    213   3            2             1000 (100%)    214   0.84         1.8           1000 (40%)    215   6.2          10           >1000    216   5            3             1000 (80%)    217   1            1             --    218   7.2          13.5         >1000    219   7            13.5         >1000    220   50           50           >1000    234   0.6          4            >1000    ______________________________________

As can be seen from the results shown in table IV, the compounds offormula (I) have an activity greater than that of the referencecompound.

They are indicated in endogenous and exogenous depressive conditions andwill be administered orally in the form of tablets, pills or capsules,at a dosage of 50 to 500 mg/day on average, of active substance.

They will also be administered in the form of an injectable solution atthe rate of 5-50 mg/day of active substance, the solvent used beingformed by binary or ternary mixtures containing for example water,polypropyleneglycol or polyethyleneglycol (quality: 300-400), or anyother physiologically acceptable solvent, the relative proportions ofthe different solvents being adjusted with respect to the doseadministered.

We claim:
 1. A compound having the formula ##STR252## is selected fromthe group consisting of ##STR253## and R is selected from the groupconsisting of cyanomethoxy, 2-cyanoethoxy, ##STR254## in which R₁₄ is H,3-Cl, 4-F, 3-CN or 3-NO₂, and ##STR255##
 2. A compound as claimed inclaim 1 in which ##STR256## is --NH₂ and R is ##STR257##
 3. A compoundas claimed in claim 1 in which ##STR258## is --NH₂.
 4. A compound asclaimed in claim 1 in which ##STR259## and R is selected from the groupconsisting of n-butoxy, 3-methylbutoxy, cyclopentylmethoxy,cyclohexylmethoxy and ##STR260## in which R₁₄ is H, 3-Cl, 3-NO₂ or 4-F.5. A compound as claimed in claim 1 in which ##STR261## is selected fromthe group consisting of ##STR262## and R is ##STR263##
 6. A compoundhaving the formula ##STR264## in which R is selected from the groupconsisting of n-butoxy, cyclopentylmethoxy, 2-cyanoethoxy and ##STR265##in which R₁₄ is 3-Cl or 3-NO₂.
 7. A compound having the formula##STR266## is selected from the group consisting of ##STR267## and R isselected from the group consisting of cyclopentylmethoxy,cyclohexylmethoxy, cyanomethoxy, 2-cyanoethoxy, ##STR268## in which R₁₄is H, 3-Cl, 4-F, 3-CN or 3-NO₂, and ##STR269##
 8. A pharmaceuticalcomposition for treating depression comprising a therapeuticallyeffective amount of a compound as claimed in claim 1 and apharmacologically acceptable carrier.
 9. A pharmaceutical compositionfor treating depression comprising a therapeutically effective amount ofa compound as claimed in claim 7 and a pharmacologically acceptablecarrier.
 10. A pharmaceutical composition for treating depressioncomprising a therapeutically effective amount of a compound as claimedin claim 6 and a pharmacologically acceptable carrier.